Invariant NKT Cells Functionally Link Microbiota-Induced Butyrate Production and Joint Inflammation

Abstract

Emerging evidence indicates that the gut microbiota contributes to the regulation of joint inflammation by modulating the function of immune cells. However, the mechanism by which the microbiota regulates joint inflammation is unclear. To address this, we investigated the effect of the gut microbiota on Ab-induced arthritis (AIA). Feeding mice a high-fiber diet attenuated AIA in a microbiota-dependent manner. Among the short-chain fatty acids produced by the microbiota, butyrate suppressed cytokine production by invariant NKT (<i>i</i>NKT) cells by inhibiting class I histone deacetylases. Furthermore, butyrate alleviated AIA in wild-type, but not <i>i</i>NKT cell-deficient Jα18 knockout (KO), mice. Adoptive transfer of butyrate-pretreated <i>i</i>NKT cells had no effect on AIA in Jα18 KO mice, whereas transfer of untreated <i>i</i>NKT cells into Jα18 KO mice restored AIA. In conclusion, our data indicate that gut microbiota-induced butyrate production attenuates AIA by inhibiting cytokine production by <i>i</i>NKT cells. Thus, the microbiota/butyrate/<i>i</i>NKT cell axis may be a therapeutic target for joint inflammation.